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Influence of a Leptin Deficiency on Testicular Morphology, Germ Cell Apoptosis, and Expression Levels of Apoptosis-Related Genes in the Mouse

GANAPATHY K. BHAT^*,

MOSHOOD O. OLATINWO^*,

DAVID SIMORANGKIR

GREGORY D. FORD

BYRON D. FORD

From the ^* Department of Physiology and the Cooperative Reproductive Science Research Center, the Department of Obstetrics and Gynecology, the Department of Anatomy and Neurobiology and the Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia; and the Department of Cell Biology and Physiology and the Specialized Cooperative Center Program in Reproduction Research, University of Pittsburgh, Pittsburgh, Pennsylvania.

Correspondence to: Dr David R. Mann, Cooperative Reproductive Science Research Center, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310 (e-mail: dmann{at}msm.edu).

Leptin-deficient (ob/ob) male mice are morbidly obese and exhibit impaired reproductive function. The objective of this study was to assess the effect of a leptin deficiency on testicular morphology, germ cell development, apoptotic activity within germ cells, and expression levels of apoptosis-related genes in the testis. Sixteen week-old ob/ob male mice (n = 8) and controls (n = 8) were killed, and their reproductive organs were weighed. Testes were processed for either histomorphological analysis (hematoxylin and eosin [H&E] staining), germ cell apoptosis assessment (deoxy-UTP-digoxigenin nick end labeling [TUNEL] method), or apoptosis-related gene expression analysis (microarray). Cross sections of the testes of leptin-deficient animals showed reduced seminiferous tubule area, fewer pachytene spermatocytes, and fewer tubules exhibiting elongated spermatids/mature spermatozoa. Condensation of germ cell nuclei and Sertoli cell vacuolization were evident in the testes of some ob/ob animals. Overall there was an elevation of apoptotic activity in the germ cells of ob/ob mice, particularly within the pachytene spermatocytes. With microarray technology, we identified 9 proapoptosis-related genes that were expressed at a significantly higher level in the testes of ob/ob mice than in the testes of the controls. Among these were members of the tumor necrosis factor receptor super family 1A and 5 (TNFR1 and 5) and peptidoglycan recognition proteins (associated with the extrinsic apoptotic pathway), and granzymes A and B, growth arrest and DNA damage inducible 45 gamma, sphingosine phosphate lyase 1, and caspase 9 (associated with the intrinsic apoptotic pathway). The results of the current study show that a leptin deficiency in mice is associated with impaired spermatogenesis, increased germ cell apoptosis, and up-regulated expression of proapoptotic genes within the testes.

     Key words: Spermatogenesis, seminiferous tubules, testis, cytomorphometry, micro array